The Bulgarian missed Saturday's Barclays Premier League win over Everton with a slight groin strain.
And whilst Sir Alex Ferguson claimed after the 1-0 triumph that he had no fitness concerns ahead of the first-leg encounter at the Veltins-Arena, Berbatov did not check in with the rest of his team-mates at Manchester Airport on Monday morning.
Although the former Tottenham man had been unlikely to start anyway, his absence is a blow as it denies Ferguson a useful attacking weapon on the bench should the match not go as planned.
He does have the in-form Javier Hernandez, who bagged his 19th goal of the season at the weekend, and Wayne Rooney, who will not remember his last trip to Gelsenkirchen with any fondness as he was sent off during England's World Cup quarter-final defeat to Portugal in 2006.
Although one of their most famous nights came against German opposition in 1999, United have not beaten a Bundesliga side in a two-legged encounter since the European Cup was revamped into the Champions League in 1992.
Bayern Munich put paid to their hopes at the quarter-final stage last year and 1997 and 2002 brought semi-final despair at the hands of Borussia Dortmund and Bayer Leverkusen respectively.
United are overwhelming favourites to book a blockbuster Wembley confrontation with either Real Madrid or Barcelona on May 28.
A shadow Schalke side lost on home soil to Kaiserslautern at the weekend to strengthen claims Ferguson's men will make it through with something to spare.
If United have been something of an enigma this term, battling to within seven points of a record 19th title despite rarely hitting the heights of previous seasons, Schalke's form is even more puzzling.
Firmly entrenched in mid-table after a disappointing Bundesliga campaign, Schalke have reserved all their best performances for Europe.
They are unbeaten since losing to Lyon in their opening group game and after dismissing a Valencia outfit that gave United two tough matches earlier this season, Schalke then slammed seven goals past holders Inter Milan at the quarter-final stage, with veteran Spain striker Raul finding the net in both legs.
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